Paclitaxel, a known TLR4 ligand, leads to activation of TLR4/MyD88-dependent pathway that mediates chemoresistance and tumor progression in epithelial ovarian carcinoma (EOC). Atractylenolide-I (AO-I), a novel TLR4-antagonizing agent, inhibits TLR4 signaling by interfering with the binding of LPS or paclitaxel to membrane TLR4 of human leukocytes. In this study, AO-I was found to attenuate paclitaxel-induced protein expression of IL-6, VEGF and survivin, and to enhance early apoptosis and growth inhibition in MyD88+ EOC cells; AO-I was shown to fit into the hydrophobic pocket of human MD-2 and to partially overlap with the binding site of paclitaxel by docking simulations, suggesting that AO-I may block the MD-2-mediated TLR4/MyD88-dependent paclitaxel signaling in MyD88+ EOC cells. Therefore, AO-I could significantly sensitize the response of MyD88+ EOC cells to paclitaxel by blocking MD-2-mediated TLR4/MyD88 signaling, and that AO-I-paclitaxel combination could be a promising strategy for the treatment of EOC with a functional TLR4/MyD88/NF-κB pathway.

Near-stoichiometric lithium tantalate ͑SLT͒ crystals were produced from congruent lithium tantalate by vapor transport equilibration, and several important optical and ferroelectric properties were measured. The effect of vapor transport conditions and surface preparation on reproducible ferroelectric engineering of SLT has been studied. Control of these effects along with dramatic decreases in the sensitivity to photorefractive damage and 532 nm absorption has allowed near-room-temperature generation of 10 W of continuous wave 532 nm radiation by second harmonic generation from 29 W of 1064 nm radiation in a 4 cm long device.

BackgroundMyD88 is an adaptor protein for TLR-4 signaling known to mediate paclitaxel resistance in epithelial ovarian carcinoma (EOC). This study examined the clinical significance of MyD88 expression in EOC.MethodsMyD88 and TLR-4 expression were examined by immunocytochemistry in 109 specimens of ovarian tissues, comprising EOC (N = 83), borderline tumors (N = 9), benign cysts (N = 9) and normal ovarian tissue (N = 8), and clinical data collected by a retrospective chart review. The correlations between MyD88 expression and clinicopathological factors and outcomes were analyzed.ResultsTLR-4 expression was detected frequently in all the ovarian tissues. Distinct MyD88 expression was showed in EOC (64 of 83, 77.1 %), in borderline tumors (5 of 9, 55.6 %) and in benign cysts (3 of 9, 33.3 %), and normal ovarian tissue showed no MyD88 expression. Positive MyD88 expression significantly correlated with shorter disease-free and overall survival for EOC (P < 0.0001 and P = 0.0031), and high MyD88 expression was significantly correlated with tumor metastasis (P = 0.0012) for EOC. Univariate and multivariate analyses revealed that MyD88 expression was an independent prognostic factor for disease-free survival and overall survival for EOC.ConclusionOur data indicate that MyD88 expression is a significantly poor prognostic factor for EOC. A better understanding of the role of MyD88 expression in disease progression and outcome may be helpful for development of novel chemotherapies for patients with EOC.

BackgroundTLR4/MD-2 complex-mediated MyD88-dependent activation of NF-κB and Akt promotes tumor-associated immunosuppression in epithelial ovarian cancer (EOC) via induction of immunesuppressive cytokines and indoleamine 2,3-dioxygenase (IDO). Atractylenolide I (AO-1) is a naturally occurring sesquiterpene lactone known to change the conformational ensemble of human MD-2 on EOC cells. This study examined the modulation by AO-1 of TLR4/MD-2 complex-mediated MyD88/NF-κB signaling.MethodsThe expression and activation of NF-κB, Akt and IDO1 by MyD88+ EOC SKOV3 cells was determined using western blot; the TLR4/MD-2 complex on SKOV3 cells and the phenotype of T lymphocytes were determined using flow cytometry; IDO activity was evaluated by measuring l-kynurenine; Immunesuppressive cytokines were detected using ELISA; T‐cell proliferation to mitogen stimulation was assessed by MTT assay; the cytotoxicity of lymphocytes and NK cells was measured using LDH-cytotoxicity assay.ResultsAO-1 could down-regulate expression of TLR4/MD-2 complex, resulting in downregulation of MyD88/NF-κB signaling and activation of NF-κB, Akt and IDO1 and secretion of IL-6, TGF-β1, VEGF and IL-17A by EOC SKOV3 cells, and further reduce increased levels of regulatory T cells (Treg cells) and improve decreased proliferative response and antitumor cytotoxicity of T lymphocytes exposed to EOC SKOV3 cell supernatant.ConclusionAO-1 may reverse EOC cell-mediated immunosuppression through blocking TLR4/MD-2 complex-mediated MyD88/NF-κB signaling.

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